The present invention relates to Vanadium (IV) compounds effective for treating tumor cells and particularly effective to induce apoptosis in leukemia cells, breast cancer cells, prostate cancer cells, and brain cancer cells.
Cancer is a major disease that continues as one of the leading causes of death at any age. In the United States alone, it is anticipated that more than half a million Americans will die of cancer in 1999. Currently, radiotherapy and chemotherapy are two important methods used in the treatment of cancer.
Considerable efforts are underway to develop new chemotherapeutic agents for more potent and specific anti-cancer therapy, presenting effective and efficient cytotoxicity against tumor cells, with minimal interference with normal cell function. Accordingly, there is an urgent need for the development and analysis of novel, effective anti-cancer agents.
A single vanadocene (IV) compound (e.g., VCp2Cl2) is reported as having biological activity.
Sakurai, et. al, BBRC, Vol. 206, p. 133 (1995) discloses an oxovanadium compound (e.g., [VO(Phen)(H2O)2](SO4)) that is active against pharyngonasal cancer as determined by a single assay.
Holmes, Ph.D. Thesis, LSU (1961) discloses oxovanadium compounds (e.g., [VO(SO4)(Phen)2] and [VO(ClO4)(Bpy)2]) but does not disclose biological data for the compounds.
Selbin, Chem. Rev., Vol. 65, p. 155 (1965) discloses oxovanadium compounds (e.g., [VO(SO4)(Phen)2] and [VO(ClO4)(Bpy)2]) but does not disclose biological data for the compounds.
The invention provides a method for treating cancer in a mammal comprising administering to the mammal in need of such treatment an effective amount of a vanadium (IV) compound; or a parmaceutically acceptable salt thereof; with the proviso that the vanadium (IV) compound is not VCp2Cl2 or [VO(Phen)(H2O)2](SO4).
The invention also provides a method for treating a mammal inflicted with cancer comprising administering to the mammal in need of such treatment an effective amount of an oxovanadium compound; or a pharmaceutically acceptable salt thereof; with the proviso that the cancer is not pharyngonasal cancer.
The invention also provides a method for treating a mammal inflicted with cancer comprising administering to the mammal in need of such treatment an effective amount of a vanadocene compound; or a pharmaceutically acceptable salt thereof; with the proviso that the vanadocene compound is not VCp2Cl2.
The invention also provides a compound of formula II: 
wherein R and R1 are each independently H, (C1-C3)alkyl, halogen, (C1-C3)alkoxy, halo(C1-C3)alkyl, cyano, (C2-C6)alkanoyloxy or nitro; X and X1 are each independently a monodentate or bidentate ligand, or no ligand is present on X1; and Y is a monodentate ligand; or a pharmaceutically acceptable salt thereof.
The invention also provides a compound of formula III: 
wherein R2and R3 are each independently H, (C1-C3)alkyl, halogen, (C1-C3)alkoxy, halo(C1-C3)alkyl, cyano, (C2-C6)alkanoyloxy or nitro; X2 and X3 are each independently a monodentate or bidentate ligand, or no ligand is present on X3; and Z is O, CH2, CH2xe2x80x94CH2 or CHxe2x95x90CH; or a pharmaceutically acceptable salt thereof; with the proviso that the compound is not [VO(Phen)(H2O)2](SO4) or [VO(SO4)(Phen)2].
The invention also provides a compound of formula IV: 
wherein R4, R5 and R6 are each independently H, (C1-C3)alkyl, halogen, (C1-C3)alkoxy, halo(C1-C3)alkyl, cyano, (C2-C6)alkanoyloxy or nitro; X4 and X5 are each independently a monodentate or bidentate ligand, or no ligand is present on X5; Y is a monodentate ligand, or no ligand is present on X5; and Y is a monodentate ligand; or a pharmaceutically acceptable salt thereof; with the proviso that the compound is not [VO(Phen)(H2O)2](SO4) or [VO(SO4)(Phen)2]. 
The invention also provides a compound of formula V: 
wherein R7 and R9 are each independently H, (C1-C3)alkyl, (C1-C3)alkoxy, or halo(C1-C3)alkyl; R8 is H, (C1-C3)alkyl, halo, (C1-C3)alkoxy, or halo(C1-C3)alkyl; Y and Y1 are each independently a monodentate or bidentate ligand; and n is 0 or 1; or a pharmaceutically acceptable salt thereof.
The invention also provides a compound of formula VII: 
wherein R1 and R2 are each independently a cyclopentadienyl ring, wherein any cyclopentadienyl ring may optionally be substituted with one or more (C1-C3)alkyl; and R10-R13 are each independently H, halo, or (C1-C6)alkyl; or a pharmaceutically acceptable salt thereof.
The invention also provides a pharmaceutical composition comprising a compound of formula II: 
wherein R and R1 are each independently H, (C1-C3)alkyl, halogen, (C1-C3)alkoxy, halo(C1-C3)alkyl, cyano, (C2-C6)alkanoyloxy or nitro; X and are each independently a monodentate or bidentate ligand; or no ligand is present on X1; and Y is a monodentate ligand, or no ligand is present on X1; and Y is a monodentate ligand or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
The invention also provides a pharmaceutical composition comprising a compound of formula III: 
wherein R2and R3are each independently H, (C1-C3)alkyl, halogen, (C1-C3)alkoxy, halo(C1-C3)alkyl, cyano, (C2-C6)alkanoyloxy or nitro; X2 and X3are each independently a monodentate or bidentate ligand, or no ligand is present on X3; and Z is O, CH2, CH2xe2x80x94CH2 or CHxe2x95x90CH; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier; with the proviso that the compound is not [VO(Phen)(H2O)2](SO4).
The invention also provides a pharmaceutical composition comprising a compound of formula IV: 
wherein R4, R5 and R6 are each independently H, (C1-C3)alkyl, halogen, (C1-C3)alkoxy, halo(C1-C3)alkyl, cyano, (C2-C6)alkanoyloxy or nitro; X4 and X5 are each independently a monodentate or bidentate ligand, or no ligand is present on X5; Y is a monodentate ligand; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier; with the proviso that the compound is not [VO(Phen)(H2O)2](SO4).